The present invention relates to a process for the preparation of imidazolyl compounds.
1,2,3,9-Tetrahydro-9-methyl-3-[2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one (ondansetron) is known from EP191562 and U.S. Pat. No. 4,695,578. These patent publications describe a general class of compounds including ondansetron and homologous compounds, their preparation and their uses as potent selective antagonists at “neuronal” 5-hydroxytryptamine receptors and in the treatment of migraine and psychotic disorders.
(10R)-5,6,9,10-Tetrahydro-10-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-pyrido[3,2,1-jk]-carbazol-11(8H)-one (cilansetron) (also known as (R)-(−)-4,5,6,8,9,10-hexahydro-10-[(2-methyl-1H-imidazol-1-yl)methyl]-11H-pyrido-[3,2,1-jk]-carbazol-11-one) is known from U.S. Pat. No. 4,939,136 (=EP 297,651), from U.S. Pat. No. 5,438,068 (=EP 601,345) and from U.S. Pat. No. 5,663,343 (=EP 768,309). The first patent describes a general class of compounds, including cilansetron and homologous compounds, their preparation and their use as 5-HT antagonists. The second patent describes the use of selected compounds of this type for the treatment of certain diseases, and the third patent describes the preparation of enantiomerically pure compounds and their hydrochloride monohydrate.
It is a common feature of the above compounds that they contain a substituted imidazolyl group attached via a methylene bridge to the α-position relative to the keto group of the carbazole system. Several possibilities for the synthesis of these compounds are described in the aforementioned patent publications. A common feature in these syntheses is that the substituted imidazolyl group is introduced by means of a Mannich reaction, followed by a deamination to yield an intermediate exomethylene compound which is reacted with the substituted imidazolyl group (see scheme 1 for an example). 
A drawback of this synthesis route is that the yield in this sequence of reaction steps is rather low. In U.S. Pat. No. 4,695,578 the first step, which is normally gives the lowest yield, is not described, and the second step (Example 7 of U.S. Pat. No. 4,695,578) gives a yield of 68%. In U.S. Pat. No. 4,939,136 the first step (Example 1c of U.S. Pat. No. 4,939,136) has a yield of 53% and the second step (Example 1d of U.S. Pat. No. 4,939,136) a yield of 87%. During scale-up it appeared that this route gives rise to the formation of a considerable amount of tar-like by-products.